期刊
COMMUNICATIONS BIOLOGY
卷 2, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-019-0420-8
关键词
-
资金
- Children with Cancer UK, Abbie's Army
- Lyla Nsouli Foundation
- Lucas' Legacy
- Fondo Alicia Pueyo
- Children's Hospital Foundation
- Xarxa de Bancs de Tumors de Catalunya (XBTC)
- Pla Director d'Oncologia de Catalunya
- ISCIII-FEDER [CP13/00189]
- Amateurs Trust
- Roemex Ltd [1097737]
- AbbVie
- Bayer Pharma AG
- Canada Foundation for Innovation, Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) [115766]
- Janssen
- MSD
- Merck KGaA
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer, Sao Paulo Research Foundation-FAPESP
- Wellcome [106169/ZZ14/Z, C13468/A14078]
- NHS
- NIHR Biomedical Research Centre at The Royal Marsden
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/ threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patientderived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据